Catalytic hydrogenation of phenylalkyl-beta-amines



hired This invention relates to a new process for the preparation of cyclohexylalkylarnines and also embraces new compounds produced therefrom. The cyclohexylalkyl amines which are produced by the process of the present invention are represented by the formula R TH where R=lower alkyl group having 16 carbon atoms or H, R =OH or H, R =lower alkyl group having 1-6 atoms or H.

More particularly, the invention relates to a process of directly hydrogenating phenylalkylamines to cyclohexylalkylamines where the amino group is ,8 to the alkyl chain. Heretofore, Zenitz, Macks & Moore (I.A.C.S., 69, 1117) reduced a number of amines in glacial acetic acid with platinum oxide using an excessive amount of the catalyst. They found it necessary to make additions of fresh catalyst in order to induce complete reduction. Zenitz et al (J.A.C.S., volume 69, page 1118, Table l, footnote) also noted that upon hydrogenation of phenylalkylamines with a platinum catalyst, a reversal in rotation was effected. Other difficulties encountered in this process were noted by Metayer, Bull. Soc. Chem., 1952, page 276. Thus, when a primary or secondary amino group is beta to the phenyl ring, high temperatures must be used which results in objectionable hydrolysis and cracking.

it is therefore an object of this invention ,to provide a means or" obtaining high yields of cyclohexylalkyl-fl-amines by direct hydrogenation of aralkylamines at moderate temperature and pressure.

it is also an object of this invention to provide a means of directly hydrogenatin aralkylamines to cyclohexylalkyl-fi-arnines without change of rotation.

A further object of this invention is to provide a method of hydrogenating aralkyl-fl-amines without the use of large quantities of catalysts.

A still further object of this invention is to provide for hydrogenation of aralkyl-B-amines without undesirable hydrolysis or cracking.

Other objects of the invention will be apparent from the detaileddescription and claims to follow.

The foregoing and other objects and advantages are accomplished when an aralkyls-amine or substituted aralkyl-B-amine is reduced with or without a solvent in the presence of ruthenium dioxide, or ruthenium or on a carrier such as ruthenium on alumina, at a temperature of about 60 to 160 C. and at a pressure of from about 1000 to 1300 pounds p.s.i.

The reaction generally is completed in less than one hour with consequent high yields. Conditions are such that a continuous process can be devised. In a likely manner, salts of the aralkylamines may be employed by the described procedure.

The cyclohexylalkylamines, produced by this process, show pharmacological activity as central nervous stimulants and vasoconstrictors. An example of such a cyclohexylalkylamine is ,8 cyclohexylisopropyhnethylamine which is known in the trade as Benzedrex.

atent 3,14,905 Patented Dec. 26, 1961 5 propylamine, and N butyl 1 cyclohexylisopropylamine. The hydrochloride salts of these compounds are also new compounds. All of these compounds, like those of the general aralkylamine class, can be used in the medical arts as central nervous stimulants and vasoconstrictors.

The following specific examples are set forth for the purpose of illustrating the invention and should not be construed to limit the invention to the precise ingredients and proportions shown.

EXAMPLE I dl-N methyl-1 -cyclohexylisopr0pylamine 74.6 g. (0.5 mole) dl-N-methyl-1-phenylisopropylamine is placed in a one-liter autoclave with 1.5 g. ruthenium dioxide catalyst and the mixture hydrogenated under pressure of 1175 pounds p.s.i. at C. When reduction is complete (which generally takes about 10 minutes), the material is filtered from the catalyst and distilled. The product dl-N-methyl-l-cyclohexylisopropylamine has a B.P.=7476 C./8 mm., and refractive index of n D=l.4570. Yield=69.9 g. (90%). The hydrochloride salt has a M.P. of 127-128 C.

EXAMPLE II dl-N-methyl-I-cycl0hexylisopropylamine 74.6 g. (0.5 mole) dl-N-methyl-l-phenylisopropyl amine is placed in a one-liter autoclave with,23 g. 5% ruthenium on alumina and the mixture hydrogenated (1.5 hrs.) under 1250 pounds p.s.i. at 90 C. The material is then decanted from under the same conditions. After reduction is complete, the mixture is filtered and washed with ethanol and the filtrate concentrated. The residue is then distilled from which dl-N-methyl-l-cyclohexylisopropylamine is recovered in a yield of 136.2 g. (88%). The product dl-N-methyl-l-cyclohexylisopropylamine has a B.P. 93-96 C./ 20 mm. The hydrochloride salt has a M.P. of -6 C.

In a similar experiment using 1% ruthenium dioxide in place of ruthenium on alumina as the catalyst, reduction is complete in 10 minutes. A 90% yield is obtained.

EXAMPLE III d-N -met hyl-1 -cycl0hexylisopropylamine d-N-methyl-l-phenylisopropylamine is hydrogenated as in Example I is less than one hour. The d-N-methyl-lcyclohexylisopropylamine boils at 78 C./8 mm, and has a refractive index of n D=1.4560. The hydrochloride salt has a M.P. of 1379 (described in literature) 138-9 and a specific rotation=+14.28.

EXAMPLE IV 1 -N-methyl-1 -cyclohexylis0propylamine EXAMPLE V dl-N-methyl-I-cycl0hexylisopropylamine hydrochloride 14.9 g. (0.08 mole) dl-N-methyl-l-phenylisopropylamine hydrochloride in 75 cc. absolute alcohol is hy drogenated with 0.3 g. ruthenium dioxide catalyst as in Yield=78%.

Example I. When reduction is complete, the solution is filtered and concentrated and 13.5 g. (88%) of the hydrochloride salt of dl-N-methyl-1-cyclohexylisopropylamine is obtained and melts at 126 C.

EXAMPLE VI d-l -cyclhexylis0pr0pylamine 67.5 g. (0.5 mole) d-l-phenylisopropylamine is hydrogenated with ruthenium catalyst as in Example I and a 66% yield of d-l-cyclohexylisopropylamine was obtained which boils at 82-85 C./ 15 mm., and has a refractive index of n D=1.4578. The hydrochloride salt melts at 190-192 C.

EXAMPLE VII [3-Cyclohexylethylamine 60.5 g. (0.5 mole) of B-phenethylamine is hydrogenated as in Example 1. Yield of the product flcyclohexylethylamine is 83%, which boils at 7l-83 C./ 13 mm., and has a refractive index of n D=1.4626.

EXAMPLE VH1 82.6 g. (0.5 mole) of 1-N-methyl-l-phenyl-l-hydroxyisopropylamine (l-ephedrine) is hydrogenated as in Example I. A 89% yield of the product l-N-rnethyl-lcyclohexyl-l-hydroxyisopropylamine is obtained which boils at 114-117 C./8 mm. The hydrochloride salt melts at 200-201 C. and has a specific rotation: -11.3.

Analysis-Calcd. For C H NO-HCl: C, 57.81%; H, 10.68%; N, 6.74. Found: C, 58.08%; H, 10.73%; N, 6.68%.

EXAMPLE IX ,B(p-Is0pr0pyl cyclohexyl) -ethylamine) 27.5 g. (0.168 mole) of 8(p-isopropyl phenyl)-ethylamine is hydrogenated as in Example I, A 70% yield of product 5(p-isopropyl cyclohexyl)-ethylamine is obtained which boils at 101 C./5 mm., and has a refractive index of n D=1.4743. Analysis Calcd. For C H N: C, 78.03%; H, 13.69%. Found: C, 77.93%; H, 13.12%. The hydrochloride salt melts at 225-227 C.

EXAMPLE X N -btttyl-1 -cycl0lzexy lisopropylam ine 68.6 g. phenyl acetone and 43.8 g. butylamine are mixed with 10 cc. alcohol and hydrogenated in the presence of 1.4 g. platinum oxide at room temperature under 48 pounds p.s.i. After reduction is complete, the mixture is distilled. A yield of 79 g. of N-butyl-l-cyclohexylisopropylamine is obtained which boils at 130-137 C./ 20 mm., and has a refractive index of n D=1.4922. Analysis Calcd. For C H N: C, 81.61; H, 11.07; N, 7.32. Found: C, 81.25; H, 10.95; N, 7.68. The hydrochloride M.P. is 172". Analysis Calcd. For C H N NCl: C, 68.55; H, 29.74; N, 6.15; CI, 15.56. Analysis found: C, 68.91; H, 29.81; N, 6.10; Cl, 15.55.

40.2 g. of N-butyl-l-phenylisopropylamine as above produced is hydrogenated in the presence of 0.8 g. ruthenium dioxide at 90 and 1000 p.s.i in the same manner as in Example I. Yield of 30.4 g. (73.6%) of N- butyl-1-cyclohexylisopropylamine is obtained after distillation, which has a boiling point of 130-1335 (20 mm.), and a refractive index of n D=1.454. Analysis Calcd. For C H N. C, 79.11; H, 13.79; N, 7.10. Analysis Found: C, 79.41; H, 14.07; N, 7.22. Hydrochloride salt, M.P. 127-8. Analysis Calcd. For c H N-HCL 4 C, 66.77; H, 12.07; N, 5.99: Analysis Found: C, 66.88; H, 11.88; N, 6.11.

Others may practice the invention in any of the numerous ways which will be suggested by this disclosure to one skilled in the art. All such practice of the invention is considered to be a part hereof provided it falls within the scope of the appended claims.

We claim: I

1. A process for preparing cyclohexylalkyl-B-amines represented by the formula wherein R is selected from the group consisting of hydrogen and lower alkyl having 1-6 carbon atoms; R is selected from the group consisting of hydroxy and hydrogen; and R is selected from the group consisting of hydrogen and lower alkyl having 1-6 carbon atoms comprising the hydrogenation of the corresponding phenylalkyl-fl-amines under a pressure of about 1000 to 1300 pounds psi. at a temperature of about 60 to 160 C. in the presence of a ruthenium catalyst selected from the class consisting of ruthenium dioxide and ruthenium present on a carrier until the reaction is complete, filtering and separating the cyclohexylalkyl-,8-arnines from the catalyst.

2. A process for preparing cyclohexylalkyl-fl-amines represented by the formula Ilia C-CH-R NH-R pounds p.s.i. at a tempe ature of about 60 to 160 C. r

in the presence of about 0.5-5% by weight of ruthenium dioxide catalyst based on the weight of the phenylalkylamine, until the reaction is complete, filtering and distilling the cyclohexylalkyl-B-amine from catalyst.

3. A process of preparing cyclohexylalkyl-B-amines wherein R is selected from the group consisting of hydrogen and lower alkyl having 1-6 carbon atoms; R; is selected from the group consisting of hydroxy and hydrogen; and R is selected from the group consisting of hydrogen and lower alkyl having 1-6 carbon atoms comprising the hydrogenation of the corresponding phenyl alkyl-fi-amines under a pressure of about 1200 to 1300 pounds p.s.i. at a temperature of about 60 to 160 C. in the presence of about 5% by weight of ruthenium on alumina catalyst based on the weight of the phenylalkyl- B-amine, until the reaction is complete, filtering and distilling the cyclohexylalkyl-[R-amines from catalyst.

4. A process for preparing ;3(p-isopropyl cyclohexyl)- ethylamine which comprises the hydrogenation of ,8(pisopropylphenyl)-ethylamine in the presence of about 1% ruthenium dioxide based on the weight of the B(p-isopropylphenyl)-ethylarnine at about 1175 pounds p.s.i. at about C. until the reaction is complete, filtering and distilling the 18(p-isopropyl cyclohexyD-ethylamine from the catalyst.

References Cited in the file of this patent UNITED STATES PATENTS Jaeger May 9, 1933 Ullyot Nov. 23, 1948 Shelton et a1. Sept. 20, 1949 Burtner et a1. Feb. 19, 1952 Kirby Aug. 12, 1952 OTHER REFERENCES 

1. A PROCESS FOR PREPARING CYCLOHEXYLALKYL-B-AMINES REPRESENTED BY THE FORMULA 